Controlling antifungal activity with light: Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors

被引:11
作者
Li, Zhuang [1 ,2 ]
Liu, Na [3 ]
Yang, Wanzhen [3 ]
Tu, Jie [3 ]
Huang, Yahui [3 ]
Wang, Wei [1 ,2 ,4 ,5 ]
Sheng, Chunquan [3 ]
机构
[1] East China Univ Sci & Technol, State Key Lab Bioengn Reactor, Sch Pharm, Shanghai 200237, Peoples R China
[2] East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China
[3] Naval Med Univ, Second Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R China
[4] Univ Arizona, Dept Pharmacol & Toxicol, Coll Pharm, Tucson, AZ 85721 USA
[5] Univ Arizona, Inst BIO5, Tucson, AZ 85721 USA
关键词
Antifungal agents; Ergosterol biosynthesis; Triazoles; Photocaged; Optical control; FLUCONAZOLE; STRATEGIES; RESISTANCE; MOLECULES; INSIGHTS; AGENTS;
D O I
10.1016/j.apsb.2023.02.008
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole la-nosterol 14a-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80 & GE; 64 mg/mL) could be effi-ciently recovered (MIC80 Z 0.5-8 mg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high -precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.
引用
收藏
页码:3080 / 3092
页数:13
相关论文
共 46 条
[1]   Visible Light Mediated Bidirectional Control over Carbonic Anhydrase Activity in Cells and in Vivo Using Azobenzenesulfonamides [J].
Aggarwal, Kanchan ;
Kuka, Timothy P. ;
Banik, Mandira ;
Medellin, Brenda P. ;
Ngo, Chinh Q. ;
Xie, Da ;
Fernandes, Yohaan ;
Dangerfield, Tyler L. ;
Ye, Elva ;
Bouley, Bailey ;
Johnson, Kenneth A. ;
Zhang, Yan Jessie ;
Eberhart, Johann K. ;
Que, Emily L. .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2020, 142 (34) :14522-14531
[2]   Current Status and Structure Activity Relationship of Privileged Azoles as Antifungal Agents (2016-2020) [J].
Ahmadi, A. ;
Mohammadnejadi, E. ;
Karami, P. ;
Razzaghi-Asl, N. .
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 2022, 59 (03)
[3]   Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia [J].
Albert, Lea ;
Xu, Jing ;
Wan, Ruiwei ;
Srinivasan, Vasundara ;
Dou, Yali ;
Vazquez, Olalla .
CHEMICAL SCIENCE, 2017, 8 (06) :4612-4618
[4]   A Benzophenone-Based Photocaging Strategy for the N7 Position of Guanosine [J].
Anhaeuser, Lea ;
Kloecker, Nils ;
Muttach, Fabian ;
Maesing, Florian ;
Spacek, Petr ;
Studer, Armido ;
Rentmeister, Andrea .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2020, 59 (08) :3161-3165
[5]  
Arendrup MC, 2013, CLIN MICROBIOL INFEC, V19, pE343, DOI 10.1111/1469-0691.12212
[6]   Light-directed maskless synthesis of peptide arrays using photolabile amino acid monomers [J].
Bhushan, KR .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2006, 4 (10) :1857-1859
[7]   o-Fluoroazobenzenes as Readily Synthesized Photoswitches Offering Nearly Quantitative Two-Way Isomerization with Visible Light [J].
Bleger, David ;
Schwarz, Jutta ;
Brouwer, Albert M. ;
Hecht, Stefan .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2012, 134 (51) :20597-20600
[8]   Light-Controlled Tools [J].
Brieke, Clara ;
Rohrbach, Falk ;
Gottschalk, Alexander ;
Mayer, Guenter ;
Heckel, Alexander .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2012, 51 (34) :8446-8476
[9]   Hidden Killers: Human Fungal Infections [J].
Brown, Gordon D. ;
Denning, David W. ;
Gow, Neil A. R. ;
Levitz, Stuart M. ;
Netea, Mihai G. ;
White, Theodore C. .
SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (165)
[10]   Phylogenomics of Sterol Synthesis: Insights into the Origin, Evolution, and Diversity of a Key Eukaryotic Feature [J].
Desmond, Elie ;
Gribaldo, Simonetta .
GENOME BIOLOGY AND EVOLUTION, 2009, 1 :364-381